Hyperhomocysteinemia is strongly associated with coronary heart disease, hypertension, and stroke, and the use of folic acid can help reduce the risks associated with hyperhomocysteinemia. But did you know that homocysteine is also inextricably linked to atrial fibrillation? Homocysteine Introduction Homocysteine (abbreviated as Hcy) is a sulfur-containing amino acid produced by demethylation of methionine in the body, and it is metabolized in the body mainly through two pathways: first, Hcy is methylated to produce methionine by methionine synthase, with methylenetetrahydrofolate as the methyl donor. Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in this process. Secondly, Hcy is metabolized by transsulfuration in combination with serine. When the above metabolic pathway is blocked, Hcy accumulates in cells and enters the circulation, causing chronic pathological damage. Hcy levels can be affected by genetic defects, nutritional factors, age, race, lifestyle habits (e.g., smoking, alcohol consumption, high methionine foods, etc.), medications (e.g., some antihypertensive and lipid-lowering drugs), and certain disease factors. Numerous studies have confirmed that Hcy is an independent risk factor for coronary artery disease, cerebrovascular and perivascular disease, and atherosclerosis. Homocysteine and atrial fibrillation A clinical study from Japan showed that circulating homocysteine levels were associated with atrial fibrillation, while homocysteine levels were associated with elevated collagen and enlarged left atrial internal diameter, all of which are concomitant manifestations of pathological atrial remodeling. Therefore, elevated blood homocysteine levels are a risk factor for recurrence after radiofrequency ablation of atrial fibrillation. Detection of homocysteine levels in blood can help in cardiovascular risk management in patients with AF. Plasma homocysteine concentrations differed among normal controls (9.6 ± 3.6 μmol/L), paroxysmal AF (10.4 ± 3.6 μmol/L), and persistent AF (12.7 ± 4.3 μmol/L, P < 0.05) and were significantly elevated in persistent AF. Another study from Naji F,et al also showed the relationship between hyperhomocysteinemia and atrial fibrillation, suggesting that homocysteine could be a prognostic factor for recurrence after electrical cardioversion of atrial fibrillation. The figure below shows the survival curves for sinus rhythm maintenance in patients with different cysteine levels. The high homocysteine group had worse sinus rhythm maintenance over the follow-up time than the low cysteine group. Homocysteine promotes the development of atrial fibrillation although how homocysteine causes atrial fibrillation is not well understood. Homocysteine activates different matrix metalloproteinases (MMPs), which regulate extracellular matrix collagen deposition, leading to structural and electrical remodeling of the atria. It has been demonstrated that homocysteine upregulates MMP2 and MMP9, both important enzymes in atrial fibrosis; also homocysteine can lead to disturbance of potassium currents in human atrial cells; in addition, homocysteine enhances oxidative stress; these are the potential pathophysiological mechanisms by which homocysteine causes atrial remodeling leading to atrial fibrillation. Homocysteine Normal Reference Values and Risks The normal reference range is 5 to 15 μmol/L in adults; however, the literature suggests that the risk of vascular stroke increases 2-fold over normal when Hcy alone is elevated with plasma >10 μmol/L, and 4-fold with >15 μmol / L. If the patient is also hypertensive, once plasma Hcy >10 μmol/L, the risk of cardiovascular and cerebrovascular events will increase significantly up to 11-30 times. At this stage, early prevention and treatment should be actively taken, while lowering blood pressure and homocysteine, so as to effectively prevent the occurrence of cardiovascular and cerebrovascular events. Homocysteine interventions Homocysteine metabolism is known to be related to the metabolism of vitamins and folic acid. When folic acid metabolism is abnormal or deficient, it can present high Hcy, which can cause structural and functional disorders of blood vessels through the inflammatory response pathway and produce cardiovascular and cerebrovascular diseases. It is known that hypertension, diabetes mellitus, cardiovascular diseases and renal dysfunction can increase Hcy in plasma. China is a high stroke occurrence country, and the occurrence of cardiovascular and cerebrovascular diseases is still increasing year by year, we should pay attention to the early detection and active intervention of the phenomenon of high Hcy in addition to the traditional risk factors, which is beneficial to the early prevention and treatment of cardiovascular and cerebrovascular diseases in China and improve the quality of healthy life. The treatment carried out for hyper-Hcy blood is mainly folic acid supplementation and vitamins B12 and B6, etc. Previous studies in people with cardiovascular disease have shown that supplementation with folic acid and related B vitamins did not reduce overall cardiovascular events, but may be able to reduce the occurrence of strokes. We are a country with a high incidence of stroke, and hypertension and hyperhcythemia are important risk factors for stroke. Our study suggests that the combination of enalapril (as an ACEI class drug, which also has the effect of inhibiting atrial remodeling and reducing atrial fibrillation) and low-dose folic acid (0.4-0.8 mg/d) to reduce Hcy treatment is safe and effective, and the effect is more pronounced in those with high Hcyemia. Therefore, it is important to focus on screening and intervention for homocysteine in patients with established AF or in patients with elevated homocysteine but without AF.